Worldwide, head and neck squamous cell carcinomas (HNSCC) constitute approximately 7% of all incident cancers, and 75% of these are seen in low- and middle-income countries. Life-style factors, in particular tobacco and alcohol consumption, are major etiological factors although an increasing number of HNSCC cases are associated with viral infections (Epstein Barr Virus and Human Papilloma Virus). Radiation therapy (RT) alone or combined with cytotoxic or molecular targeted agents is a mainstay as definitive treatment for previously untreated locally advanced disease. This therapy offers organ and functional preservation in many cases with an approximate 30 to 50% of cases obtaining longterm loco-regional tumor control. Accelerated RT, that is increasing the weekly delivered radiation dose above the conventional 10 Gy per week, has been shown in a large number of randomized controlled trials to be associated with an improved efficacy to toxicity ratio relative to standard fractionation provided a careful balance between total dose, dose per fraction and overall treatment time is chosen. The Danish Head and Neck Cancer Group trial DAHANCA 6/7 tested a schedule of accelerated normofractionated radiation therapy for HNSCC delivering 6 fractions of 2.0 Gy per week to a total dose of 66-68 Gy. This schedule gave a 10% improvement in loco-regional tumor control compared with the same dose delivered with 5 fractions per week. The DAHANCA 6/7 schedule was tested in the IAEA ACC trial, comparing again 6 vs. 5 fractions per week but allowing the total dose to range from 66 Gy to 70 Gy. The outcome of the IAEA ACC trial also showed a significant 13% improvement in loco-regional control in the accelerated arm. Thus, accelerating RT by delivering 6 fractions per week may reasonably be considered a standard of care for definitive RT alone. Clinical evidence points in the direction of a 4 week accelerated, hypofractionated schedule as being a radiobiologically interesting alternative to accelerated schedules using more fractions for treatment of HNSCC. A series of exploratory calculations suggested that an attractive schedule could be 55 Gy in 20 fractions (2.75 Gy per fraction) delivered over 4 weeks and this schedule was chosen for the test arm of HYPNO. There is historical experience with this schedule in the North of UK and in many countries in the British Commonwealth. The aim of this study is to test whether this resource-sparing 4-week course of accelerated hypofractionated radiotherapy is non-inferior to radiotherapy delivering 33 fractions over 5.5 weeks.